Composition and method for treatment of warts

ABSTRACT

Provided is a composition comprising 5-FU and salicylic acid. This composition is useful as a treatment for warts. As opposed to conventional compositions and methods, this composition need only be applied once a day. Also provided are methods for the preparation and use of the composition for treatment of warts.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation application of U.S. Ser. No.11/037,403 filed Jan. 18, 2005, the disclosure of which is herebyexpressly incorporated by reference.

FIELD OF THE INVENTION

Embodiments of the present invention relate generally to compositionsand methods for treating warts on an individual, and more particularlyto a sustained release composition so that the composition need only beapplied once a day.

BACKGROUND OF THE INVENTION

The present invention relates to a composition for treating wartsincluding, but not limited to, common warts, plantar warts, flat warts,and filiform warts. The present invention is not to be limited totreating plantar warts. However, as a manner of convenience and toexplain some of the types of problems that the present inventionaddresses, problems associated with the current modalities of plantarwarts are discussed.

Plantar warts are epidermal lesions caused by an infection by the humanpapilloma virus (HPV), a double-stranded DNA virus. HPV has over a 100subtypes, but those most found in plantar warts are HPV 1, 2, 4, and 10.Plantar warts are generally benign and usually self-limiting lesions,but are often painful and can be debilitating. The incidence of plantarwarts is 1 to 2 percent in the general population, with 60% of casesresolving spontaneously within a two year period. Although multipletreatments have been proposed over the years, to date there is nouniformly effective treatment for warts. Aggressive treatments for therecalcitrant wart include surgical excision, laser, and cryotherapytreatments. Because these approaches are often painful and do notguarantee success, doctors and patients may opt for a less invasivetreatment, or patients may try to treat themselves at home.

The most common at home treatment for warts is a non-prescriptionsalicylic acid preparation, usually a gel or cream, containingconcentrations ranging from 10-60% salicylic acid. Salicylic acid actsin a catalytic manner breaking down protein (keratin) found in the wartand the thick layer of dead skin on top of the wart. To be effective,these preparations need to be applied several times a day over a seriesof weeks, even months. As such, efficacy is dependent on patientcompliance with repeated applications. Even with patient compliance,less than half who use salicylic acid experience success. Therefore,alternative treatments have been proposed.

Several topical preparations are known in the art for use in thetreatment of warts. As already noted, known treatments aredisadvantageous in that they typically require repeated dailyapplications. Further, with many of these treatments, the patient needsto debride the wart between applications to provide maximum contact andpenetration of the medication to the wart.

U.S. Pat. No. 6,599,513 is directed to emulsion formulations that aredisclosed as optionally including various anti-psoriasis actives. Theseformulations require the presence of substantially intact oil bodiesderived from a cell.

Another home remedy for the treatment of warts is duct tape. Unlike mostwart treatments, duct tape does not require repeated daily applicationsand works simply by occluding the wart, thereby creating a maceratingand keratolytic environment. However, duct tape alone may not provideresolution of warts.

For these and other reasons, there is a need for the present invention.

Accordingly, it is an object of the present invention to provide acomposition effective for the treatment of warts.

Another object of the present invention is to provide a compositioneffective for the treatment of warts that requires only once dailyapplication.

Still another object of the present invention is to provide a methodusing a composition that is effective in the treatment of warts.

A further object of the present invention is to provide a kit effectivefor the treatment of warts that comprises a composition containing 5-FUand salicylic acid.

The method and means of accomplishing each of the above objectives aswell as others will become apparent from the detailed description of theinvention which follows hereafter.

SUMMARY OF THE INVENTION

The invention is based upon the observation that a composition of thecombination of 5-FU and salicylic acid in a pharmacologically acceptedtopical vehicle are effective in treating warts. Methods of treating awart of an individual are provided. A therapeutically effective amountof a composition comprising 5-FU and salicylic acid is topically appliedto a wart on an individual. Also provided is a kit for treating a warton an individual including a quantity of a composition comprising 5-FUand salicylic acid and an applicator. A method for the preparation of acomposition of 5-FU and salicylic acid is provided.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

As used herein, the “treatment” refers to any process, action,application, therapy, or the like, wherein an individual with a wart, issubject to the present invention with the object of improving theindividual's condition, directly or indirectly.

As used herein, the term “therapeutically effective amount” means thatamount of a composition of the present invention effective in reducingthe size of a wart. The present invention is directed to apharmaceutical composition for the treatment of warts. The presentinventors have discovered that the combination of 5-FU and salicylicacid in a gel-like vehicle is useful in treating warts. Accordingly, amethod for administering the composition for treatment of warts is alsoencompassed by the invention. The composition of this invention isfurther distinguished from prior art wart treatments in allowing foronce daily administration.

In accordance with preferred embodiments of the invention, there isprovided a composition comprising 5-FU and salicylic acid, present in atherapeutically effective amount and in a pharmaceutically acceptablevehicle for topical treatment of warts. The 5-FU is typically present inan amount ranging from about 0.5 to 5.0% by weight of the composition.The salicylic acid is typically present in an amount ranging from about10.0 to 25.0% by weight of the composition. The concentrations of thesedrugs may vary from these ranges due to a variety of factors, includingsize and location of the wart, weight and age of the patient, cost, etc.

Without wishing to be bound by any specific theory, it is believed thatthe 5-FU and salicylic acid of the invention act in a synergistic mannerto provide the desired resolution of a wart. Together, the salicylicacid removes the keratin of the wart and surrounding skin to improvepenetration of the 5-FU, which inhibits viral replication of the HPVwhich causes wart formation. The synergistic effect provides acomposition for treating warts that is superior to using either 5-FU orsalicylic acid alone.

In contrast to other known treatments, the composition need only beapplied daily for the treatment of warts. It is believed that thecomposition is capable of sustained release throughout the day. Inaccordance with principles of Fickian diffusion, as the compositiondries and the concentration of active ingredients increase, the betterthe penetration of active ingredients into the treatment site.

In addition to the 5-FU and salicylic acid, the composition mayadditionally include an organic solvent, an adhesive, plasticizer, and awater swellable polymer. The organic solvent may be one or more ofdimethylsulfoxide (DMSO), N,N′-dimethylacetamide (DMA),N′N′-dimethylformamide (DMF), dioxane, tetraglycol, or the like. DMSO ispreferred in this respect. The solvent should be present in aconcentration sufficient to dissolve the 5-FU, but is typically presentin a concentration ranging from about 5-50% by weight, with about 15-25%by weight being preferred and about 20% by weight being most preferredsince this concentration provides a good consistency. Otherconcentrations may be preferred, however, depending on the consistencydesired, i.e. the more solvent added, the thinner the compositionbecomes and vice versa.

Appropriate adhesives for use in the invention include, but are notlimited to, polyvinyl alcohol, polyethylene oxides, polyethylene glycolsof molecular weight 3350 and higher, hydroxypropylcellulose, andpovidone. Polyvinyl alcohol is preferred. The adhesive is typicallypresent in an amount from about 10 to 75% by weight, preferably about45-55% by weight, and most preferably about 50% by weight of thecomposition. This latter concentration is preferred since it provides agood consistency. Again, however, more or less adhesive may be includeddepending on the consistency desired, i.e. the more adhesive added, thethicker the composition and vice versa.

The composition may optionally include a plasticizer. Suitableplasticizers are typically high-boiling, water-soluble organic compoundscontaining hydroxyl, amide, or amino groups. Such plasticizers include,but are not limited to, soy, egg or synthetic lecithin, ethylene glycol,tetraethylene, hexamethylene, nonaethylene glycol, formamide,ethanolamine salts, water, glycerin, or combinations thereof, withlecithin being a preferred plasticizer. Such plasticizers are well knownin the art. It is believed that the plasticizer serves the dual roles ofa penetration enhancer for the active ingredients, as well as enhancingthe flexibility of the adhesive. A plasticizer is therefore preferablyincluded in the formulation to provide these benefits. The plasticizeris typically present in the composition in an amount ranging from about0.4-2.0% by weight, with about 1-2% by weight being preferred, and about0.9% by weight being most preferred.

The composition may also include a water swellable polymer which acts asan extender, and serves to thicken the composition. Such water swellablepolymers are well known in the art and include, but are not limited to,microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, methyl ethyl cellulose, sodiumcarboxymethylcellulose, gums, carboxyvinyl polymer, hydroxyethylcellulose, cornstarch, casein, urea, dextrin, and fume silica. Thefiller is typically present in an amount from about 1-10% by weight,preferably about 3-6% by weight, with about 4.67% by weight being mostpreferred. It should be understood that the water swellable polymerconstitutes the remainder of a given composition after other ingredientsand their respective amounts are determined.

The ingredients of this invention when combined form topical adhesivegels. These gels, while clear, may optionally include some amounts ofprecipitated active ingredient. The presence of this precipitated drugdoes not interfere with the activity of the compositions in treatingwarts. Unlike the compositions of U.S. Pat. No. 6,599,513, thecompositions of the present invention do not require the use ofsubstantially intact oil bodies and, in fact, may be substantially freeof intact oil bodies. As used herein, the term “substantially free ofintact oil bodies” means the composition contain insufficient amounts ofintact oil bodies so as to create an emulsion.

The ingredients can all be combined together to form a workablecomposition. In a preferred method of manufacture, the 5-FU is firstcombined with the solvent so as to dissolve the 5-FU. Salicylic acid isthen added, followed by the remaining ingredients.

The compositions of the invention may further include a variety ofsubstances, including suitable stabilizers, buffers, thickeners,lubricants, wetting, and dissolving agents as well as colorings,moisturizers, preservatives, and fragrances. These minors are added insmall amounts and are conventionally known in pharmaceutical formulationwork to enhance elegance. Such minors should comprise less than about 1%of the overall composition.

Other actives may also be used in this invention so long as they aresafe for external use and compatible with the other ingredients in theformulation. Examples of such actives include, but are not limited to,antibiotics, antivirals, anti-inflammatories, antioxidants, analgesics,etc.

The present invention is further directed to a method of treating warts.The method of the invention comprises topically applying to a wart on anindividual a therapeutically effective amount of the compositions of theinvention. The composition may be applied using an applicator, forexample, a swab, sponge, finger cot or a toothpick. In one embodiment ofthe method, the composition is applied using the side of a flattoothpick to “frost” the wart. While the compositions of this inventionare adhesive in and of themselves, in another embodiment of theinvention, the method further comprises occluding the wart with anoccluding agent to aid the composition's absorption into the wart,protect the composition from rubbing off, and also further keratolyticactivity. Many occluding agents are known to those skilled in the art.These include, but are not limited to, bandages, plastic wrap, andadhesive tape, for example, duct tape.

When applied, the compositions are wet, but soon dry to form a film.Unlike prior art wart treatments, the compositions of this inventionneed only be applied once a day to achieve therapeutic results. However,the composition is safe for application multiple times a day if thepatient so chooses, although no therapeutic or cost benefit is achievedby doing so. For best results, the wart treatment composition of thisinvention is applied once daily at approximately the same time each day.The present inventor has surprisingly found that applying thecomposition at bedtime rather than in the morning provides even bettertherapeutic results. The treatment site is preferably washed with mildsoapy water and dried prior to reapplication. Daily applications shouldpreferably continue for a period of time of at least one week, or untilthe patient can no longer visualize the wart. This latter time periodwill vary greatly based on the size of the wart.

The following examples are offered to illustrate but not limit theinvention. Thus, it is presented with the understanding that variousformulation modifications as well as method of delivery modificationsmay be made and still are within the spirit of the invention.

EXAMPLE 1 Wart Treatment Composition

Ingredient Quantity (in grams) Polyvinyl (PVA) alcohol powder 12.00Edetate disodium USP (dihydrate) powder 0.05 Lecithin soya granules 1.80Water paraben preserved liquid 100.00

Manufacturing Procedure:

1. Disperse PVA powder and EDTA in room temperature water for ½ hourunder moderate stir speed using a magnetic stir bar.

2. Heat the dispersion to 80° C. and continue mixing until all globuleshave dissolved.

3. Discontinue heat, but continue stirring on the plate until a cleargel solution forms. This may require sitting at room temperature toeliminate the air bubbles. Once the gel is moderately warm (not hot),disperse the lecithin with stirring until a uniform dispersion forms.

EXAMPLE 2 Wart Treatment Composition

Ingredient Quantity 5-fluorouracil granules 2.00 g Salicylic acid powder17.00 g DMSO liquid 20.00 ml Microcrystalline cellulose NF (PH-105)powder 4.66667 g PVA-LS (12/18.8)% gel 100.00 gManufacturing Procedure: 1. Take an appropriately sized beaker with aplastic stir rod.

2. Add a magnetic stir bar, DMSO and 5-fluorouracil, stir untilcompletely dissolved.

3. Add salicylic acid and let dissolve, then remove magnetic stir bar.

4. Add ½ total weight of PVA-LS, and stir with rod.

5. Add Avicel pH-105 and stir.

6. QS with PVA-LS to final volume and stir well

EXAMPLE 3 Polyvinyl Alcohol 10% Gel

Ingredient Quantity Polyvinyl alcohol powder 10.00 g Edetate disodiumUSP (dihydrate) powder 0.05 g Water paraben preserved liquid 100.00 ml

Manufacturing Procedure:

1. Disperse PVA powder in room temperature water for ½ hour undermoderate stir speed using a magnetic stir bar.

2. Heat the dispersion to 60-80° C. and continue stirring for another ½hour.

3. Discontinue heat, but continue stirring on the plate until clear gelsolution forms.

EXAMPLE 4 pH's of Wart Treatment Compositions

The compositions described in Examples 1-3 were tested by a certifiedmedical technologist to determine their respective pH's.

The composition of Example 1 manufactured in accordance with thedescribed process had a pH of 5.05. The composition of Example 2manufactured in accordance with the described process has a pH of 2.70.The composition of Example 3 manufactured in accordance with thedescribed process had a pH of 4.87.

A preferred formulation of the invention known as WartPEEL has a pH of2.7. The formulation for WartPEEL is as follows:

Ingredient Quantity Salicylic acid powder, U.S.P. powder 17 g5-Fluorouracil granules 2 g Lecithin soya granules 1.8 g Avicel PH-105(microcrystalline cellulose NF) 4.6667 g Dimethyl sulfoxide USP (DMSO)20 ml Polyvinyl alcohol 12% gel 54.5333 g

Several physicians have used the WartPEEL formulation with greatsuccess:

Dr. Richard H. Weiner, DPM, a board certified podiatrist with 35 yearsof experience found the WartPEEL product to be an effective treatmentfor verruca plantaris. The product is well-received by his patients whoexhibit good compliance and minimal discomfort.

Dr. Annette Wagner, MD, a dermatologist certified in Pediatrics,Dermatology, and Pediatric Dermatology, notes that WartPEEL is, “aneffective first line treatment for children with multiple hand and feetwarts that are too numerous to treat with cryotherapy.”

Dr. Kristi Harvey, MD, board-certified in Pediatrics, has beenprescribing WartPEEL to patients for treatment of warts for more thanfive years. She has not received any feedback from patients regardinglocal irritation or pain as a result of using WartPEEL, and haswitnessed “countless examples” of where her patients have used WartPEELfor treatment of their warts and their large warts have completely fadedin reasonable periods of time, while small warts disappear after lessthan five applications of WartPEEL.

Dr. Rebecca Cummins, MD, certified dermatologist, notes that she hasfound WartPEEL to be very beneficial in treating stubborn plantar warts.In this regard, she has used WartPEEL as lone therapy and in conjunctionwith other wart treatments, including liquid nitrogen, imiquimod,squaric acid, and cimetidine.

Dr. James Mahoney, DPM, FACFAS, board-certified in podiatric surgerywith nearly 30 years of experience, states he is so impressed with thepreliminary results achieved using WartPEEL that he now uses it with hismost resistant wart cases as a first-line treatment.

It should be appreciated that minor dosage and formulation modificationsof the composition and the ranges expressed herein may be made and stillcome within the scope and spirit of the present invention.

Having described the invention with reference to particularcompositions, theories of effectiveness, and the like, it will beapparent to those of skill in the art that it is not intended that theinvention be limited by such illustrative embodiments or mechanisms, andthat modifications can be made without departing from the scope orspirit of the invention, as defined by the appended claims. It isintended that all such obvious modifications and variations be includedwithin the scope of the present invention as defined in the appendedclaims. The claims are meant to cover the claimed components and stepsin any sequence which is effective to meet the objectives thereintended, unless the context specifically indicates to the contrary.

1. A composition for treatment of warts comprising: from 0.5 to 5.0% byweight 5-fluorouracil (5-FU); from 10.0 to 25.0% by weight salicylicacid; from 5 to 50% by weight of DMSO; from 1-10% by weight of awater-swellable polymer; and from 10-75% by weight of an adhesive;whereby the composition is a sustained release topical gel thatphysically releases salicylic acid onto the wart for removal of keratinof the wart and surrounding skin to allow penetration of the 5-FU intothe wart.
 2. The composition of claim 1 further including from 0.4 to2.0% by weight lecithin; and further providing that the adhesive ispolyvinyl alcohol gel.
 3. The composition of claim 1 comprising 2-5% byweight 5-FU.
 4. The composition of claim 1 comprising 2% by weight 5-FU.5. A composition for treatment of warts comprising: from 0.5 to 5.0% byweight 5-fluorouracil (5-FU); from 10.0 to 25.0% by weight salicylicacid; from 5 to 50% by weight of DMSO; from 1-10% by weight of awater-swellable polymer; and from 10-75% by weight of an adhesive;whereby the composition is a sustained release topical gel, saidcomposition being acidic.